Hydroxamic acid derivatives

ABSTRACT

Compounds having therapeutic utility are of the formulawherein NB2 is heterocycloalkyl and R1 and R2 are each various substituents or a cyclic group.

This application is a National Stage Application of InternationalApplication Number PCT/GB00/04865, filed Dec. 18, 2000 published,pursuant to PCT Article 21(2), in English.

FIELD OF THE INVENTION

This invention relates to hydroxamic acid derivatives, and to their usein medicine.

BACKGROUND OF THE INVENTION

Metalloproteinases, including matrix metalloproteinase (MMP), (humanfibroblast) collagenase, gelatinase and TNF convertase (TACE), and theirmodes of action, and also inhibitors thereof and their clinical effects,are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, thecontents of which are incorporated herein by reference. MMP inhibitorsmay also be useful in the inhibition of other mammalianmetalloproteinases such as the adamalysin family (or ADAMs) whosemembers include TNF convertase (TACE) and ADAM-10, which can cause therelease of TNFα from cells, and others, which have been demonstrated tobe expressed by human articular cartilage cells and also involved in thedestruction of myelin basic protein, a phenomenon associated withmultiple sclerosis.

Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenase, stromelysin and gelatinase, have been shown to inhibit therelease of TNF both in vitro and in vivo. See Gearing et al (1994),Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561;GB-A-2268934; and WO-A-9320047. All of these reported inhibitors containa hydroxamic acid zinc-binding group, as do the imidazole-substitutedcompounds disclosed in WO-A-9523790. Other compounds that inhibit MMPand/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687,WO-A-9603571 1, WO-A-96035712 and WO-A-96035714.

Further, somewhat related compounds are disclosed in U.S. Pat. No.5,892,112, WO-A-9724117 and FR-A-2597865.

SUMMARY OF THE INVENTION

Compounds according to the invention are of formula (I):

wherein

R¹ is a group (optionally substituted with R³) selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyland C₁₋₆ alkyl-heterocycloalkyl; and

R² is H or C₁₋₆ alkyl;

or CR¹R² is cycloalkyl or heterocycloalkyl optionally substituted withR³ or a group (optionally substituted with R³) selected from C₁₋₆ alkyl,aryl, C₁₋₆ alkyl-aryl, heteroaryl and C₁₋₆ alkyl-heteroaryl;

R³ is OR⁷, COR⁷, CO₂R⁶, CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂,NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸ and SO₂N(R⁷)₂; or cycloimidyl (optionallysubstituted with R⁴)

R⁴ is C₁₋₆ alkyl;

B—N—B is heterocycloalkyl optionally substituted with R⁵ or ═NOR⁵;

R⁵ is H, R⁶ or a group (optionally substituted with R⁶) selected fromC₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆alkyl-heterocycloalkyl;

R⁶ is H or a group selected from N(R⁷)₂ NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸,NR⁷SO₂R⁸, OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸ and SO₂N(R⁷)₂;

R⁷ is H or a group selected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl, wherein said group isoptionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸,NR⁶R⁸ or SO₂NR⁴R⁸, and for each case of N(R⁷)₂ the R⁷ groups are thesame or different or N(R⁷)₂ is heterocycloalkyl optionally substitutedwith R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁶R⁸ or SO₂NR⁴R⁸; and

R⁸ is C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl;

and the salts, solvates, hydrates, N-oxides, protected amino, protectedcarboxy and protected hydroxamic acid derivatives thereof.

DESCRIPTION OF THE INVENTION

Preferred compounds of the invention are those wherein R¹ is C₁₋₆ alkylor CR¹R² is heterocycloalkyl.

The compounds of the Examples are particularly preferred.

It will be appreciated that the compounds according to the invention cancontain one or more asymmetrically substituted carbon atoms. Thepresence of one or more of these asymmetric centers in a compound offormula (I) can give rise to stereoisomers, and in each case theinvention is to be understood to extend to all such stereoisomers,including enantiomers and diastereomers, and mixtures including racemicmixtures thereof

It will further be appreciated that the compounds according to theinvention may contain an oxime. This oxime can give rise to geometricalisomers, and in each case the invention is to be understood to extend toall such isomers and mixtures thereof As used in this specification,alone or in combination, the term “C₁₋₆alkyl” refers to straight orbranched chain alkyl moiety having from one to six carbon atoms,including for example, methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl, hexyl and the like.

The term “C₂₋₆ alkenyl” refers to a straight or branched chain alkylmoiety having two to six carbon atoms and having in addition one doublebond, of either E or Z stereochemistry where applicable. This term wouldinclude for example, vinyl, 1-propenyl, 1- and 2-butenyl,2-methyl-2-propenyl etc.

The term “C₂₋₆ alkynyl” refers to a straight or branched chain alkylmoiety having two to six carbon atoms and having in addition one triplebond. This term would include for example, ethynyl, 1-propynyl, 1- and2-butynyl, 1-methyl-2-butynyl etc.

The term “cycloalkyl” refers to a saturated alicyclic moiety having fromthree to six carbon atoms and includes for example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. The term“cycloalkenyl” refers to an alicyclic moiety having from three to sixcarbon atoms and having in addition one double bond. This term includes,for example, cyclopentenyl and cyclohexenyl.

The term “heterocycloalkyl” refers to a saturated heterocyclic moietyhaving from two to six carbon atoms and one or more heteroatom from thegroup N, O, S (or oxidised versions thereof) which may be optionallybenzofused at any available position. This includes for exampleazetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, benzodioxoleand the like. For the group NB₂, which is heterocycloalkyl, thesaturated heterocyclic moiety must contain at least one N atom. Thisincludes, for example, azetidinyl, pyrrolidinyl, piperidinyl and thelike.

The term “heterocycloalkenyl” refers to an alicyclic moiety having fromthree to six carbon atoms and one or more heteroatoms from the group N,O, S and having in addition one double bond. This term includes, forexample, dihydropyranyl.

The term “aryl” refers to an aromatic carbocyclic radical having asingle ring or two condensed rings, optionally substituted with an arylgroup substituent. This term includes, for example phenyl or naphthyl.

The term “heteroaryl” refers to aromatic ring systems of five to tenatoms of which at least one atom is selected from O, N and S, andoptionally substituted with an aryl group substituent. This termincludes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl andthe like.

The term “aryl group substituent” refers to a substituent chosen fromhalogen, CN, CF₃, CHF₂, CH₂F, OCF₃, OCF₂H, OCFH₂ and NO₂.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “benzofused” refers to the addition of a benzene ring sharing acommon bond with the defined ring system.

The term “cycloimidyl” refers to a saturated ring of five to ten atomscontaining the atom sequence —C(═O)NC(═O)—. The ring may be optionallybenzofused at any available position. Examples include succinimidoyl,phthalimidoyl and hydantoinyl.

The term “optionally substituted” means optionally substituted with oneor more of the groups specified, at any available position or positions.The terms “protected amino”, “protected carboxy” and “protectedhydroxamic acid” mean amino, carboxy and hydroxamic acid groups whichcan be protected in a manner familiar to those skilled in the art. Forexample, an amino group can be protected by a benzyloxycarbonyl,tert-butoxycarbonyl, acetyl or like group, or may be in the form of aphthalimido or like group. A carboxyl group can be protected in the formof a readily-cleavable ester such as the methyl, ethyl, benzyl ortert-butyl ester. A hydroxamic acid may be protected as either N orO-substituted derivatives, such as O-benzyl orO-tert-butyldimethylsilyl.

Salts of compounds of formula (I) include pharmaceutically-acceptablesalts, for example acid addition salts derived from inorganic or organicacids, such as hydrochlorides, hydrobromides, p-toluenesulphonates,phosphates, sulphates, perchlorates, acetates, trifluoroacetates,propionates, citrates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

Salts may also be formed with bases. Such salts include salts derivedfrom inorganic or organic bases, for example alkali metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

When the “protected carboxy” group in compounds of the invention is anesterified carboxyl group, it may be a metabolically-labile ester offormula CO₂R⁹ where R⁹ may be an ethyl, benzyl, phenethyl, phenylpropyl,“α or β-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl orpivaloylmethyl group.

Compounds of the general formula (I) may be prepared by any suitablemethod known in the art and/or by the following processes. It will beappreciated that, where a particular stereoisomer of formula (I) isrequired, the synthetic processes described herein may be used with theappropriate homochiral starting material, and/or isomers can be resolvedfrom mixtures using conventional separation techniques (e.g. HPLC).Thecompounds according to the invention may be prepared by the followingprocess. In the description and formulae below the groups R¹, R² and Bare as defined above, and Y is NHOH, except where otherwise indicated.It will be appreciated that functional groups, such as amino, hydroxylor carboxyl groups, present in the various compounds described below,and which it is desired to retain, may need to be in protected formbefore any reaction is initiated. In such instances, removal of theprotecting group may be the final step in a particular reactionsequence. Suitable protecting groups for such functionality will beapparent to those skilled in the art. For specific details see Greene T.W. et al, “Protective Groups in Organic Synthesis”, Wiley Interscience(1999).

Thus, for example, compounds of the invention may be prepared by thefollowing general route:

Acids of formula (IV), where X is for example an alkoxy group, e.g.methoxy or ethoxy or a chiral auxiliary, e.g.R-4-benzyl-oxazolidin-2-one, may be prepared by deprotection of an esterof formula (VI) (where W is for example a tert-butyl or benzyl group)using, for example, an acid such as trifluoroacetic acid or by reactionwith hydrogen in the presence of an appropriate catalyst such aspalladium on carbon. Esters of formula (VI) may be prepared by reactionof an ester of formula (VII), wherein Z is an appropriate leaving groupsuch as a halide, for example a bromide, or an alkyl or aryl sulfonatesuch as methanesulfonate, with an ester of formula (VIII). Suitableconditions for this reaction include the treatment of compound (VIII)with a strong organic base, such as n-butyllithium or sodiumhexamethyldisilazide, in an inert solvent such as tetrahydrofuran at anappropriate temperature such as −78° C. to 0° C., followed by the slowaddition of (VII).

Many esters of formulae (VII) and (VIII) or amines of formula (V) areknown in the literature or may be prepared by standard methods known tothose skilled in the art or by methods described in the exampleshereinafter.

The acids of formula (IV) may be used to prepare compounds of formula(III) by reaction with an amine of formula B₂NH (V) using standardmethods known to those skilled in the art, for example, by in situactivation of an acid of formula (IV) using for example a diimide suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,advantageously in the presence of catalyst such as4-dimethylaminopyridine, in a halogenated hydrocarbon, e.g.dichloromethane, followed by subsequent addition of an amine of formula(V). Alternatively, an acid of formula (IV) may be activated, forexample by conversion to an acid halide such as an acid chloride byreaction with a halogenating agent such as oxalyl chloride, in thepresence of a catalyst such as N,N-dimethylformamide in a halogenatedhydrocarbon, e.g. dichloromethane. The acid chloride (which may or maynot be isolated) can then be reacted with an amine of formula (V) in thepresence of an amine base such as triethylamine in a halogenatedhydrocarbon, e.g. dichloromethane.

Carboxylic acids of formula (II) may be prepared by deprotection of asuitably protected carboxylic acid of formula (III), where X is removedfor example by lithium hydroxide in the case of an alkyl ester, e.g.ethyl or lithium hydroxide/hydrogen peroxide in the case of a chiralauxiliary such as R-4-benzyl-oxazolidin-2-one, using appropriate solventand temperature conditions such as those described in the exampleshereinafter.

The acids of formula (II) may be used to prepare compounds of formula(I) under conditions well known in the literature. For example,treatment of acids of formula (II) with oxalyl chloride in an inertsolvent (such as dichloromethane) gives an intermediate acid chloride,which may or may not be isolated, but which in turn is reacted withhydroxylamine at a suitable temperature such as room temperature to givethe desired hydroxamic acids (I). Alternatively, an acid of formula (II)maybe activated in situ using for example a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,advantageously in the presence of a catalyst such as a N-hydroxycompound, e.g. N-hydroxybenzotriazole, using suitable conditions, e.g.in N,N dimethylformamide at −10° C., prior to the subsequent addition ofa suitably protected hydroxylamine such as tert-butyldimethyl silylhydroxylamine and maybe an an amine base such as N-methylmorpholinefollowed by warming to ambient temperature. The protecting group mayberemoved using appropriate conditions, such as water ortetrabutylammonium fluoride and acetic acid in tetrahydrofuran at 0° C.,to yield the desired hydroxamic acids of formula (I).

Compounds of formula (I) may also be prepared by interconversion ofother compounds of formula (I). Thus, for example, a compound of formula(I) wherein is a C₁₋₆ alkyl group may be prepared by hydrogenation(using palladium on carbon in suitable solvent, such as an alcohol, e.g.ethanol) of a compound of formula (I) wherein R¹ is a C₂₋₆ alkenylgroup.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

The compounds according to the invention exhibit in vitro inhibitingactivities with respect to the stromelysin, collagenase, gelatinase,ADAM or ADAM-TS enzymes. Compounds according to the invention may alsoexhibit in vitro inhibition of membrane shedding events known to bemediated by metalloproteinases, for example, α-APP, ACE, TGF-α, TNF-α,Fas ligand, selectins, TNFR-I, TNFR-II, CD30, I1-6R, CD43, CD44, CD16-I,CD16-II, Folate receptor, CD23, or IL-1RII.

The activity and selectivity of the compounds may be determined by useof the appropriate enzyme inhibition test, for example as described inExamples A-M of WO-A-9805635, by the assay for the inhibition of CD23shedding described in WO-A-9924399 or by the assay of TNF RI sheddingdescribed in WO-A-0056704.

This invention also relates to a method of treatment for patients(including man and/or mammalian animals raised in the dairy, meat or furindustries or as pets) suffering from disorders or diseases which can beattributed to metalloproteinases.

Accordingly, the compounds of formula (I) can be used among other thingsin the treatment of osteoarthritis and rheumatoid arthritis, and indiseases and indications resulting from the over-expression of thesematrix metalloproteinases such as found in certain metastatic tumourcell lines.

As mentioned above, compounds of formula (I) are useful in human orveterinary medicine since they are active as inhibitors of TNF and MMPs.Accordingly in another aspect, this invention concerns:

a method of management (by which is meant treatment or prophylaxis) ofdisease or conditions mediated by TNF and/or MMPs in mammals, inparticular in humans, which method comprises administering to the mammalan effective amount of a compound of formula (I) above, or apharmaceutically acceptable salt thereof, and

a compound of formula (I) for use in human or veterinary medicine,particularly in the management (by which is meant treatment orprophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and

the use of a compound of formula (I) in the preparation of an agent forthe management (by which is meant treatment or prophylaxis) of diseasesor conditions mediated by TNF and/or MMs.

The disease or conditions referred to above include inflammatorydiseases, autoimmune diseases, cancer, cardiovascular diseases, diseasesinvolving tissue breakdown. Appropriate diseases include rheumatoidarthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer'sdisease, stroke, vasculitis, Crohn's disease, ulcerative colitis,multiple sclerosis, periodontitis, gingivitis and those involving tissuebreakdown such as bone resorption, haemorrhage, coagulation, acute phaseresponse, cachexia and anorexia, acute infections, HIV infections,fever, shock states, graft versus host reactions, dermatologicalconditions, surgical wound healing, psoriasis, atopic dermatitis,epidermolysis bullosa, tumour growth, angiogenesis and invasion bysecondary metastases, ophthalmological disease, retinopathy, cornealulceration, reperfusion injury, migraine, meningitis, asthma, rhinitis,allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestiveheart failure, endometriosis, atherosclerosis, endosclerosis,aspirin-independent anti-thrombosis, systemic lupus erythematosus andsolid organ transplant.

Compounds of formula (I) may also be useful in the treatment of pelvicinflammatory disease (PID), age-related macular degeneration andcancer-induced bone resorption. Further, they can be used in thetreatment of lung diseases, e.g. selected from cystic fibrosis, adultrespiratory distress syndrome (ARDS), emphysema, bronchitisobliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis(PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).

For the treatment of all disorders or diseases previously indicated, thecompounds of formula (I) may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats etc, the compounds of the invention are effective in the treatmentof humans.

The pharmaceutical composition containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavouring agents, colouring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example corn starch, or alginic acid; bindingagents, for example starch, gelatin or acacia, and lubricating agents,for example magnesium stearate, stearic acid or talc. The tablets may beuncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere in the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one ormore colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified, for example sweetening, flavouringand colouring agents, may also be present.

The pharmaceutical compositions oft he invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be in a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of formula (I) may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc containing the compounds of Formula (I) are employed. For thepurposes of this specification, topical application includes mouthwashes and gargles.

Dosage levels of the order of from about 0.05 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove—indicated conditions (about 2.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day (about 0.5 mg to about 3.5 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay vary from about 5 to about 95% of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofactive ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following Examples illustrate the invention.

INTERMEDIATE 12-(2-(4-(4-Chlorobenzoyl)piperidin-1-yl)-2-oxoethyl)-4-methylpentanoicAcid Methyl Ester

4-(4-Chlorobenzoyl)piperidine (0.2 g) was added to a solution of methyl3-isobutylsuccinic acid (0.15 g) and EDC (0.25 g) in dichloromethane (10ml) and the solution was stirred for 18 h, then washed with water (10ml), aqueous citric acid (10 ml), saturated sodium bicarbonate (10 ml)and brine (10 ml), dried over magnesium sulphate (1 g) and evaporated togive the title compound (0.25 g) as a colourless solid.

R_(f) 0.45 (ether)

INTERMEDIATE 22-(2-(4-(4-Chlorobenzoyl)piperidin-1-yl)-2-oxoethyl)-4-methylpentanoicAcid

A solution of Intermediate 1 (0.25 g) in tetrahydrofuran (5 ml) wastreated with a solution of lithium hydroxide (0.1 g) in water (5 ml) andthe mixture was stirred at room temperature for 24 hours, thenevaporated in vacuo, the aqueous residue washed with ether (2×5 ml),acidified with dilute HCl and extracted with ethyl acetate (3×10 ml).The solvent was washed with water (10 ml) and brine (10 ml), dried overmagnesium sulphate (1 g) and evaporated to give the title compound (0.18g) as a colourless solid.

R_(f) 0.28 (EtOAc)

INTERMEDIATE 32-(2-(4-(4-Chlorobenzoyl)piperidin-1-yl)-2-oxoethyl)-4-methylpentanoicacid N-tert-butyldimethylsilyloxyamide

A solution of Intermediate 2 (0.18 g) in DCM (10 ml) was treated withEDC (0.15 g) and O-tert-butyldimethylsilylhydroxylamine (0.15 g) and themixture was stirred for 18 h, then washed with water (10 ml) and brine(10 ml), dried over magnesium sulphate (1 g) and evaporated to give thetitle compound as a colourless solid (0.12 g).

R_(f) 0.64 (EtOAc)

INTERMEDIATE 4 4R-Benzyl-3-(3-methylbutyryl)oxazolidin-2-one

n-Butyllithium (33.0 ml, 1.6M) was added to a solutionof4R-benzyloxazolidin-2-one (9.0 g) intetrahydrofuran (100 ml) at −78°C. and the solution was stirred for 30 min, then a solution ofisovaleryl chloride (6.1 g) was added dropwise over 20 min. Theresulting suspension was stirred for 2 h, then aqueous ammonium chloride(50 ml) was added and the mixture evaporated in vacuo. The product wascollected by filtration, washed with water (15 ml) and dried in vacuo togive the title compound (13 g) as a colourless solid.

R_(f) 0.45 (2:1 ether/hexane)

INTERMEDIATE 53S-(4R-Benzyl-2-oxo-oxazolidine-3-carbonyl)-4-methyl-pentanoic Acidtert-Butyl Ester

Sodium hexamethyldisilazide (1.0 M in tetrahydrofuran, 23.0 ml) wasadded to a solution of Intermediate 4 (6.0 g) in tetrahydrofuran at −78° C. and the solution was stirred for 30 min, then a solution oftert-butyl bromoacetate (3.7 ml) in tetrahydrofuran was added dropwise.The mixture was stirred for 30 min, then allowed to warm to roomtemperature and ammonium chloride solution (5 ml) added. The mixture wasevaporated in vacuo and the aqueous residue extracted withdichloromethane (3×10 ml). The solvent was washed with water (15 ml),brine (15 ml), dried over magnesium sulphate (5 g) and evaporated togive the title compound (8.6 g) as a colourless solid.

R_(f) 0.65 (3:2 hexane/ether)

INTERMEDIATE 63S-(4R-Benzyl-2-oxo-oxazolidine-3-carbonyl)-4-methyl-pentanoic acid

Trifluoroacetic acid (10 ml) was added to a solution of Intermediate 5(8.6 g) in dichloromethane (50 ml) and the solution was stirred at roomtemperature for 2 h, then evaporated in vacuo and the residue azeotropedwith heptane to dryness. The residue was dissolved in aqueous sodiumbicarbonate (10 ml) and washed with ether (2×10 ml), the aqueous layeracidified with citric acid and extracted with dichloromethane (3×10 ml).The solvent was washed with water (10 ml) and brine (10 ml), dried overmagnesium sulphate (5 g) and evaporated to give the title compound as acolourless oil (7.2 g) which crystallised slowly on standing.

R_(f) 0.45 (ether+1% AcOH)

INTERMEDIATE 7 4-(4-Chlorophenylsulfanyl)piperidine-1-carboylic Acidtert-Butyl Ester

Di-tert-carbonate (9 g) was added to a stirred suspensionof4-bromopiperidine (10 g) in dichloromethane (200 ml). Triethylamine(6.3 ml) was added and the reaction stirred at room temperature for 30min, before being washed with aqueous citric acid (5%, 100 ml), water(100 ml) and brine (100 ml). The organic layer was dried over magnesiumsulphate (5 g), before the solvent was removed in vacuo to yield acolourless oil which was taken up in N,N-dimethylformamide (50 ml).4-Chlorothiophenol (5.8 g) and potassium carbonate (5.3 g) were addedand the reaction heated at 80 ° C. for 6 h. On cooling the reaction wasdiluted with water (50 ml) and extracted with ether (3×50 ml). Thecombined organic extracts were washed with water (100 ml), brine (100ml), dried over magnesium sulphate (2 g), and the solvent removed invacuo to yield the title compound (14.2 g) as a yellow oil.

R_(f) 0.43 (2:1 hexane/ether)

INTERMEDIATE 8 4-(4-Chlorobenzenesulfonyl)piperidine-1-carboxylic Acidtert-Butyl Ester

Oxone (25 g) and sodium acetate (9 g) in water (200 ml) were added to asolution of Intermediate 7 (14.2 g) in methanol (300 ml) and thereaction stirred at room temperature for 6 h. The methanol was removedin vacuo and the resulting slurry extracted with dichloromethane (2×100ml). The combined organic extracts were washed with aqueous sodiumhydroxide (2M, 100 ml), water (100 ml), brine (100 ml), dried overmagnesium sulphate (3 g) and the solvent removed in vacuo. The oilyresidue was crystallized from ether/hexane to yield on filtration anddrying in vacuo the title compound as a white solid (7.2 g).

R_(f) 0.29 (ether)

INTERMEDIATE 9 4-(4-Chlorobenzenesulfonyl)piperidine

Trifluoroacetic acid (15 ml) was added to a solution of Intermediate 8(6.5 g) in dichloromethane (40 ml) and the solution was stirred at roomtemperature for 3 h, then evaporated in vacuo and the residue azeotropedwith heptane to dryness. The residue was dissolved in aqueous sodiumbicarbonate (10 ml) and washed with ether (2×10 ml), the aqueous layeracidified with citric acid and extracted with dichloromethane (3×10 ml).The dichloromethane extracts were combined and washed with water (10ml), brine (10 ml), dried over magnesium sulphate (5 g) and evaporatedto give the title compound as a white solid (5.0 g).

R_(f) 0.25 (EtOAc with 1% ammonium hydroxide)

INTERMEDIATE 10 4(6-Fluorobenzo[d]isoxazol-3-yl)piperidine-1-carboxylicAcid tert-Butyl Ester

Di-tert-carbonate (0.9 g) was added to a stirred suspension of(2,4-difluorophenyl)piperidin-4-ylmethanone (1 g) in dichloromethane (30ml). Triethylamine (0.62 ml) was added and the reaction stirred at roomtemperature for 2 h, before being washed with aqueous citric acid (5%,20 ml), water (20 ml) and brine (20 ml). The organic layer was driedover magnesium sulphate (1 g), before the solvent was removed in vacuoto yield a yellow oil which was taken up in ethanol (20 ml). Acetic acid(2 ml) and aqueous hydroxylamine (2 ml) were added and the reactionstirred at room temperature for 2 h. Water (50 ml) was added and thereaction extracted with dichloromethane (3×30 ml). The combined organicextracts were washed with water (50 ml), brine (50 ml), dried overmagnesium sulphate (2 g), and the solvent removed in vacuo to yield ayellow oil which was taken up in N,N-dimethylformamide (20 ml) andsodium hydride (0.12 g, 60%) added. The reaction was heated to 80° C.for 3 h, before on cooling being diluted with water (40 ml), andextracted with EtOAc (3×20 ml). The combined organic extracts werewashed with water (30 ml), brine (30 ml), dried over magnesium sulphate(1 g) and the solvent removed in vacuo to yield the title compound (0.7g) as a white solid.

R_(f) 0.63 (ether)

INTERMEDIATE 11 6-Fluoro-3-piperidin-4-ylbenzo[d]isoxazole

Trifluoroacetic acid (8 ml) was added to a solution of Intermediate 10(0.7 g) in dichloromethane (20 ml) and the solution was stirred at roomtemperature for 3 h, then evaporated in vacuo and the residue azeotropedwith heptane to dryness. The residue was dissolved in methanol (4 ml),diluted with ether (ca 12 ml) and the solid that formed was collected byfiltration. On drying in vacuo, the title compound was yielded as a pinksolid (0.65 g).

R_(f) 0.25 (7% MeOH/dichloromethane with 1% ammonium hydroxide).

INTERMEDIATE 12 4-(Naphthalen-2-yloxy)piperidine-1-carboxylic Acidtert-Butyl Ester

To a stirred solution of 2-naphthol (2.9 g) and4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) intetrahydrofuran (30 ml) at 0° C. was added triphenylphosphine (5.2 g)and diethyl azodicarboxylate (3.2 ml). The reaction was allowed to warmto room temperature and stirred for 16 h. The solvent was removed invacuo and the slurry taken up in EtOAc (30 ml) and washed with aqueoussodium hydroxide (1M, 2×30 ml), water (30 ml) and brine (30 ml). Theorganic extract was diluted with hexane (50 ml), and the precipitateswere removed by filtration, and the filtrate dried over magnesiumsulphate (1 g). The solvent was removed in vacuo to yield the titlecompound as a white solid (3.4 g).

R_(f) 0.63 (2:1 ether/hexane).

INTERMEDIATE 13 4-(Naphthalen-2-yloxy)piperidine Hydrochloride

Trifluoroacetic acid (20 ml) was added to a solution of Intermediate 12(3.4 g) in dichloromethane (60 ml) and the solution was stirred at roomtemperature for 1 h, then evaporated in vacuo and the residue azeotropedwith heptane to dryness. The residue was dissolved in aqueous sodiumhydroxide (1M, 10 ml) and washed with ether (2×10 ml), the aqueous layeracidified with citric acid and extracted with dichloromethane (3×10 ml).The solvent was washed with water (10 ml), brine (10 ml), dried overmagnesium sulphate (2 g) and evaporated to give a yellow oil. The oilwas taken up in methanol (5 ml) and hydrogen chloride in ether (2M, 15ml) was added. The precipitate was collected by filtration and dried invacuo to yield the title compound as a white solid (2.6 g).

R_(f) 0.05 (10% MeOH/dichloromethane)

INTERMEDIATE 141-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-4-[4-(4-chlorobenzoyl)-piperidin-1-yl]-2S-isopropylbutane-1,4-dione

EDC (0.20 g) was added to a solution of Intermediate 6 (0.32 g) indichloromethane (20 ml) and the solution was stirred for 30 min, then asolution of 4-(4-chlorobenzoyl)piperidine (0.25 g) was added and themixture was stirred overnight. The solution was washed with aqueouscitric acid (10 ml), aqueous sodium bicarbonate (10 ml) and brine (10ml), dried over magnesium sulphate (1 g) and evaporated to give thetitle compound (0.50 g) as a colourless gum.

R_(f) 0.47 (ether).

Similarly prepared were:

INTERMEDIATE 151-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-4-[4-(4-chlorophenoxy)-piperidin-1-yl]-2S-isopropylbutane-1,4-dione

From (4R, 3R)3-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-4-methylpentanoic acid (0.62g) and 4-chlorophenoxypiperidine (0.58 g), the title compound wasyielded as a colourless solid (1.1 g).

R_(f) 0.48 (ether)

INTERMEDIATE 161-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-4-[4-(4-chlorophenyl)-piperazin-1-yl]-2S-isopropylbutane-1,4-dione

From Intermediate 6 (1.7 g) and 4-chlorophenylpiperazine (1.4 g), thetitle compound was yielded as a colourless foam (2.50 g).

R_(f) 0.39 (ether)

INTERMEDIATE 171-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-4-[4-(4-chlorobenzene-sulfonyl)piperidin-1-yl]-2S-isopropylbutane-1,4-dione

From Intermediate 6 (1.02 g) and Intermediate 9 (0.85 g), the titlecompound was yielded as a white foam (1.46 g).

R_(f) 0.73 (ether)

INTERMEDIATE 181-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-4-[4-(6-fluorobenzo-[d]isoxazol-3-yl)piperidin-1-yl]-2S-isopropylbutane-1,4-dione

From Intermediate 6 (0.16 g) and Intermediate 11 (0.18 g), the titlecompound was yielded as a yellow oil (0.12 g).

R_(f) 0.45 (2:1 ether/hexane)

INTERMEDIATE 191-(4R-Benzyl-2-oxo-oxazolidin-3-yl)-2S-isopropyl-4-[4-(naphthalen-2-yloxy)piperidin-1-yl]butane-1,4-dione

From Intermediate 6 (0.31 g) and Intermediate 13 (0.26 g), the titlecompound was yielded as a yellow oil (0.32 g).

R_(f) 0.63 (2:1 ether/hexane)

INTERMEDIATE 202S-{2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid

Lithium hydroxide (0.15 g) in water (5 ml) was added to a solution ofIntermediate 14 (1.8 g) in tetrahydrofuran (20 ml), water (5 Ml) andaqueous hydrogen peroxide (8M, 1.3 ml) at 0° C. and the mixture wasstirred for 1 8 h. Sodium sulfite (5 g) in water (10 ml) was added andthe mixture was evaporated in vacuo. The aqueous residue was washed withether (2×10 ml), then acidified with citric acid and extracted withdichloromethane (2×20 ml), the combined dichloromethane extracts werewashed with water (30 ml), brine (30 ml), dried over magnesium sulphate(1 g) and evaporated to give the title compound (0.65 g) as a colourlesssolid.

R_(f) 0.25 (EtOAc)

Similarly prepared were:

INTERMEDIATE 212S-{2-[4-(4-Chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid

From Intermediate 15 (1.1 g), to yield the title compound as acolourless solid (0.65g).

R_(f) 0.40 (EtOAc)

INTERMEDIATE 222S-{2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylbutyricAcid

From Intermediate 16 (2.50 g) as a colourless solid (0.80 g).

R_(f) 0.20 (ether+1% AcOH)

INTERMEDIATE 232S-{2-[4-(4-Chlorobenzenesulfonyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid

From Intermediate 17 (1.46 g), to yield the title compound as a whitesolid (0.6 g).

R_(f) 0.43 (EtOAc)

INTERMEDIATE 242S-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yI]-2-oxoethyl}-3-methylbutyricAcid

From Intermediate 18 (112 mg), to yield the title compound as a whitesolid (0.6 g).

R_(f) 0.25 (ether)

INTERMEDIATE 252S-3-Methyl-2-{2-[4-(naphthalen-2-yloxy)piperidin-1-yl]-2-oxoethyl}butyricAcid

From Intermediate 19 (0.32 g), to yield the title compound as a beigeoil (0.12 g).

R_(f) 0.35 (2:1 EtOAc/hexane)

EXAMPLE 12S-{2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-4-methylpentanoicAcid N-hydroxy Amide

A solution of Intermediate 3 (0.12 g) was stirred in DCM (10 ml) and asolution of HCl in ether (2 ml) was added dropwise. The mixture wasstirred for 10 min, then diluted with hexane (10 ml) and the productisolated by filtration to give the title compound as colourless solid.

R_(f) 0.35 (10% MeOH/CH₂Cl₂).

MS 379, 381 (M+1)

EXAMPLE 22S-{2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid N-hydroxy Amide

EDC (0.20 g) and N-hydroxybenzotriazole (0.15 g) were added to asolution of Intermediate 20 (250 mg) in DMF (10 ml) at −10° C. and themixture was stirred for 30 min, then a solution of tert-butyldimethylsilyl hydroxylamine (120 mg) and N-methylmorpholine (200 μl) was added.The mixture stirred for 48 h, then added to water (10 ml) and extractedwith EtOAc (2×10 ml). The solvent was washed with water (10 ml), aqueoussodium bicarbonate (10 ml), brine (10 ml), dried over magnesium sulphate(1 g) and evaporated and the residue purified by chromatography (6%MeOH/DCM) to give the title compound (120 mg) as colourless solid.

R_(f) 0.42 (6% MeOH/CH₂Cl₂);

MS 380 (M⁺).

Similarly prepared were:

EXAMPLE 32S-{2-[4-(4-Chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid N-hydroxy Amide

From Intermediate 21 (93 mg), to yield the title compound as acolourless solid (30 mg).

R_(f) 0.37 (10% MeOH/CH₂Cl₂);

MS 368 (M⁺).

EXAMPLE 42S-{2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylbutyricAcid N-hydroxy Amide

From Intermediate 22 (0.80 g), to yield the title compound as a beigefoam (0.43 g).

R_(f) 0.37 (6% MeOH/CH₂CI₂);

MS 353 (M⁺).

EXAMPLE 52S-{2-[4-(4-Chlorobenzenesulfonyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid N-hydroxy Amide

From Intermediate 23 (0.80 g), followed by purification by flashchromatography on silica (eluent 6% MeOH/CH₂Cl₂) to yield the titlecompound as a white solid (0.20 g).

R_(f) 0.29 (6% MeOH/CH₂Cl₂);

MS 417 (M⁺).

EXAMPLE 62S-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricAcid N-hydroxy Amide

From Intermediate 24 (0.70 g), followed by purification by flashchromatography on silica (eluent 6 % MeOH/CH₂Cl₂) to yield the titlecompound as a white solid (0.43 g).

R_(f) 0.33 (5% MeOH/CH₂CI₂);

MS 380 (M+1).

EXAMPLE 72S-N-Hydroxy-3-methyl-2-{2-[4-(naphthalen-2-yloxy)-piperidin-1-yl]-2-oxo-ethyl}butyramide

From Intermediate 25 (0.10 g), followed by purification by flashchromatography on silica (eluent 10% MeOH/CH₂Cl₂) to yield the titlecompound as a white solid (0.035 g).

R_(f) 0.37 (10% MeOH/CH₂Cl₂);

MS 385(M+1).

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is a moiety (optionally substituted with R³) selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl; andR² is H or C₁₋₆ alkyl; or CR¹R² is cycloalkyl or heterocycloalkyloptionally substituted with R³ or a moiety, optionally substituted withR³, selected from the group consisting of C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl and C₁₋₆ alkyl-heteroaryl; R³ is OR⁷, COR⁷,CO₂R⁶, CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸,S(O)₀₋₂R⁸ and SO₂N(R⁷)₂; or cycloimidyl (optionally substituted withR⁴); R⁴ is C₁₋₆ alkyl; B—N—B is heterocycloalkyl optionally substitutedwith R⁵ or ═NOR⁵; R⁵ is H, R⁶ or a moiety selected from the groupconsisting of C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyltycloalkyl, heterocycloalkyl andC₁₋₆ alkyl-heterocycloalkyl, wherein said moiety is, optionally,substituted with R⁶; R⁶ is H or a moiety selected from the groupconsisting of N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, OR⁷,COR⁷, CO₂R⁴ CON(R⁷)₂, S(O)₀₋₂R⁸ AND SO₂N(R⁷)₂; R⁷ is H or a moietyselected from the group consisting of C₁₄ alkyl, aryl, C₁₋₆ alkyl, c₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl,wherein said moiety is optionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸,CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁶R⁸ or SO₂NR⁴R⁸, and for each case of N(R⁷)₂ theR⁷ groups are the same or different or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸,NR⁶R⁸ or SO₂NR⁴R⁸; and are the same or different or N(R⁷)₂ isheterocycloalkyl optionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸,OR⁸, CONR⁴R⁸, NR⁶R⁸ or SO₂NR⁴R⁸; and R⁸ is C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl; or a salt, hydrate,N-oxide, protected amino, protected carboxy or protected hydroxamic acidderivative thereof.
 2. A compound of claim 1, wherein R¹ is C₁₋₆ alkyl.3. A compound of claim 1, wherein R² is H.
 4. A compound of claim 1,wherein CR¹R² is optionally substituted cycloalkyl or heterocycloalkyl.5. A compound of claim 1 which is in the form of a single enantiomer ordiastereomer.
 6. A compound of claim 1, which is selected from the groupconsisting of: a.2S-{2-[4-(4-chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-4-methylpentanoicacid N-hydroxy amide, b.2S-{2-[4-(4-cblorobenzoyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, and c.2S-{2-[4-(4-chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, d. 2S-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylbutyric acid-N-hydroxy amide.
 7. A compound ofclaim 1, selected from2S-{2-[4-(4-chlorobenzenesulfonyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide,2S-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, and2S-N-hydroxy-3-methyl-2-{2-[4-(naphthalen-2-yloxy)-piperidin-1-yl]-2-oxo-ethyl}butyramide.8. A compound of claim 2, wherein R² is H.
 9. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.
 10. A method of treatingmetalloprotease associated disorders or diseases in an individualcomprising the administration of therapeutically effective amount of acomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier to said individual; wherein saidindividual suffers from metalloprotease associated disorders ordiseases.
 11. The method of claim 10, wherein said condition is selectedfrom the group consisting of cancer, asthma, inflammation, inflammatoryconditions, autoimmune disease, infectious disease, ocular disease, andage-related macular degeneration.
 12. The method of claim 10, whereinsaid compound is selected from the group consisting of: a.2S-{2-[4-(4-chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-4-methylpentanoicacid N-hydroxy amide, b.2S-{2-[4-(4-chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, and c.2S-{2-[4-(4-chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid-N-hydroxy amide, d. 2S-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylbutyric acid-N-hydroxy amide.
 13. The method ofclaim 11, wherein said compound is selected from the group consistingof: a.2S-{2-[4-(4-chlorobenzenesulfonyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, b.2S-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide, and c.2S-N-hydroxy-3-methyl-2-{2-[4-(naphthalen-2-yloxy)-piperidin-1-yl]-2-oxoethyl}butyramide.14. The method of claim 10, wherein said compound is in the form of asingle enantiomer or diastereomer.
 15. The method of claim 10, whereinsaid compound is2S-{2-[4-(4-chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-4-methylpentanoicacid N-hydroxy amide.
 16. The method of claim 10, wherein said compoundis 2S-{2-[4-(4-chlorobenzoyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide.
 17. The method of claim 10, wherein said compoundis 2S-{2-[4-(4-chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide.
 18. The method of claim 10,, wherein said compoundis 2S-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoeythyl}-3-methylbutyricacid N-hydroxy amide.
 19. The method of claim 10, wherein said compoundis2S-{2-[4-(4-chlorobenzenesulfonyl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide.
 20. The method of claim 10, wherein said compoundis2S-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl]-2-oxoethyl}-3-methylbutyricacid N-hydroxy amide.
 21. The method of claim 10, wherein said compoundis2S-N-hydroxy-3-methyl-2-{2-[4-(naphthalen-2-yloxy)-piperidin-1-yl]-2-oxoethyl}butyramide.